1. Field of the Invention
The present invention relates to novel chiral phosphines for applications in asymmetric catalysis. More particularly, the present invention relates to transition metal complexes of these chiral phosphine ligands. The transition metal complexes according to the present invention are useful as catalysts in asymmetric reactions.
2. Description of the Prior Art
Several families of conformationally rigid chiral bisphosphines suitable for use in transition metalatalyzed enantioselective transformations are known. The present invention discloses asymmetric catalysts based on chiral bidentate phosphines with multi-stereogenic centers in the backbone. Conformational analysis leads to the result that one of the stereochemical arrangements of the many diastereomers is the most enantioselective ligand for transition metal-catalyzed asymmetric reactions. A common feature of these ligands is that appropriate stereogenic centers in these ligands can restrict conformational flexibility of the ligands and thus the efficiency of chiral transfer can be enhanced through the ligand rigidity.
Molecular chirality plays a very important role in science and technology. The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometime has deleterious side effects. During the last few decades, asymmetric catalysis has been developed as effective method for the production of enantiomerically pure compounds.
Development of chiral phosphine ligands has played a significant role in various types of transition metal-catalyzed asymmetric synthesis (H. Brunner, W. Zettlmeier, Handbook of Enantioselective Catalysis with Transition Metal Compounds, Vol. 2, Ligands-References, VCH Verlagsgesellschaft, weinheim, 1993, p359). Especially, chiral diphosphines of C2-symmetry are of special interest due to their high enantioselectivities in asymmetric reactions. Chiral 1,4-bisphosphines, such as, DIOP (H. B. Kagan, T.-P. Dang, J. Am. Chem. Soc. 1972, 94, 6429), BPPM (K. Achiwa, J. Am. Chem. Soc. 1976, 98, 8265; and I. Ojima, N. Yoda, Tetrahedron Lett. 1980, 21, 1051.), BICP (G. Zhu, P. Cao, Q. Jiang, X. Zhang, J. Am. Chem. Soc., 1997, 119, 1799) have been developed for transition metal-catalyzed asymmetric catalysis. 
Although these ligands are effective for some asymmetric transformations, there are some areas in where these ligands are not efficient in their activity and selectivity. Thus, the design and synthesis of new chiral phosphine ligands that are effective in the more difficult asymmetric transformations remain important and challenging endeavors. The present invention discloses design and synthesis of novel chiral bisphosphines based on the conformational analysis.
The relationship between catalyst conformation and product configuration has been studied before. In general, the observed high asymmetric induction is attributed to the well define formed chiral conformation of the chelate. Based on a number of experiments, enantioselectivity with DIOP is not high in many asymmetric reactions. A possible explanation for this observation might be that the chiral centers are too far and the seven-membered chelate ring of DIOP (1) bound to transition metal (e.g., rhodium) is too conformationally flexible (the transfer of backbone chirality to the phenyl groups on the phosphine goes through a methylene group). 
To overcome this drawback, Kagan synthesized ligand 2 in which there are two more chiral centers closer to the phosphorus atom (H. B. Kagan, J. C. Fiaud, C. Hoornaert, D. Meyer, J. C. Poulin, Bull. Soc. Chim. Belg. 1979, 88, 923). Unfortunately, in this case the enantioselectivity for asymmetric hydrogenation of dehydroaminoacid was substantially lower than in the case of DIOP. We reasoned that the poor selectivity may be caused by the two newly introduced methyl groups which may have an axial position in the seven-membered chelate ring influencing enantioselectivity (R. Selke, M. Ohff, a. Riepe, Tetrahedron 1996, 52, 15079). This explanation suggests that the revised configuration of the two chiral centers in ligand 3 (R,S,S,R)-DIOP* (star) will force every substituent to have an equatorial position and form a well defined conformation chelated with Rh so that a high enantioselectivity can be achieved. We have found that bisphosphine 3 is a much more effective ligand than DIOP (1) and 2 for asymmetric hydrogenation reactions. This led to the conclusion that appropriate conformation of chiral ligands is the key to the high enantioselectivity, thereby providing a foundation on which the new chiral phosphines of the present invention are based.
Thus, while the hydrogenation of dehydroaminoacids (an electron-withdrawing alkene) with the Rh-based catalyst gave poor enanatioselectivity {(a) Berens, U.; Leckel, D.; Oepen, S. C. J. Org. Chem. 1995, 60, 8204. (b) Berens, U.; Selke, R. Tetrahedron: Asymmetry 1996, 7, 2055}., we have achieved outstanding results for hydrogenation and simple enamides (an electron rich alkene) with 3 (R,S,S,R)-DIOP*.
The present invention includes a ligand selected from the group consisting of compounds represented by I through XI: 
wherein Xxe2x80x2 is selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, hydroxy, alkoxy, aryloxy, siloxy, thioalkoxy, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, amido, ester, reverse ester, keto, halo silyl and SH;
wherein Rxe2x80x2 is selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino and amido;
wherein each X, Z and Zxe2x80x2 is independently selected from the group consisting of: O, NH, NR, CH2, CHR, CR2, Cxe2x95x90O, S, SO2, and SO;
wherein each Zxe2x80x3 is independently selected from the group consisting of: N, P, CH, and CR;
wherein each R1, R2, R3 and R4 is independently selected from the group consisting of: H, alkyl, aryl, substituted alkyl, substituted aryl and OR;
wherein each Y and Yxe2x80x2 is independently selected from the group consisting of: a diol protecting group residue, O, CO, C(OR)2, CH(OR), CH2, CHR, CR2, CR2, NR, SO2, xe2x80x94(CH2)nxe2x80x94 wherein n is 0 or an integer from 1 to 8, xe2x80x94(CH2)nQ(CH2)mxe2x80x94 wherein each n and m is independently an integer from 1 to 8, divalent phenyl, substituted divalent phenyl, 2,2xe2x80x2-divalent-1,1xe2x80x2-biphenyl, substituted 2,2xe2x80x2-divalent-1,1xe2x80x2-biphenyl, 2,2xe2x80x2-divalent-1,1xe2x80x2-binaphthyl, substituted 2,2xe2x80x2-divalent-1,1xe2x80x2-binaphthyl, 1,1xe2x80x2-ferrocene, substituted 1,1xe2x80x2-ferrocene, wherein the substituent in each of said substituted divalent phenyl, biphenyl, binaphthyl and ferrocene is one or more moiety each independently selected from the group consisting of: alkyl, aryl, aralkyl, alkaryl, alkenyl, akkynyl, F, Cl, Br, I, OH, OR, SH, SR, COOH, COOR, SO3H, SO3R, PO3H2, PO3HR, PO3R2, NH2, NHR, NR2, PR2, AsR2, SbR2 and nitro; and
wherein each R is independently selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, fluoroalkyl, perfluoroalkyl and xe2x80x94CRxe2x80x22(CRxe2x80x22)qQ(CRxe2x80x22)pRxe2x80x2 wherein each q and p is independently an integer from 1 to 8, Q is selected from the group consisting of: O, S, NR, PR, AsR, SbR, divalent aryl, divalent fused aryl, divalent 5-membered ring heterocycle and divalent fused heterocycle.
The present invention also includes a process for preparing a ligand enantiomer in high enantiomeric purity. The process comprises the steps of:
contacting an enantiomer of tartaric acid diester and a diol protecting group in the presence of an acid catalyst to produce a bis-protected tartrate diester;
contacting said bis-protected tartrate diester and a reducing agent to convert the ester functional groups in said tartaric acid diester to a diol;
converting said diol to a sulfonate ester; and
displacing the sulfonate group in said sulfonate ester with lithium diphenylphosphinide to produce the ligand enantiomer.
The present invention further includes a catalyst prepared by a process comprising contacting a transition metal salt, or a complex thereof, and a ligand selected from the group consisting of compounds represented by I through XI, as described above.
The present invention still further includes a process for preparation of an asymmetric compound using a catalyst according to the present invention. The process comprises contacting a substrate capable of forming an asymmetric product by an asymmetric reaction and a catalyst prepared by a process comprising contacting a transition metal salt, or a complex thereof, and a ligand selected from compounds represented by I through XI, as described above. The transition metal complexes of the chiral ligands of the present invention produce chiral products with an extremely high enantioselectivity. For example, ruthenium complex of chiral (R,S,S,R)-DIOP* ligand reduces enamides with 99% enantioselectivity to produce the corresponding amine in a 99% ee.